Ion channels are involved in the regulation of cellular excitability. A recently identified novel sodium (Na+) channel (NNC), highly enriched in the locus coeruleus (LC), may contribute to the intrinsic electrical properties of these neurons. Studies have demonstrated that alterations in LC neuronal activity, via activation of a sodium conductance that resembles NNC in many ways, occur following opiate administration. To better understand the role of NNC in vivo, studies will examine the regional profile of NNC mRNA and protein in brain. Biochemical studies will investigate the phosphorylation potential of NNC. In situ hybridization and Western blot analysis will determine whether morphine exposure induces alterations in NNC expression. To more directly assess the role of NNC in the LC, and to explore the possibility that this channel is a mediator in opiate dependence, I will begin work to create a line of NNC null ('knockout') mutant mice. Together, these integrated, multidisciplinary studies will advance my training as well as elucidate the role of NNC in regulating the excitability of LC neurons under normal conditions and after chronic opiate dependence.